Alterations in expression levels of deafness dystonia protein 1 affect mitochondrial morphology

TY - JOUR

T1 - Alterations in expression levels of deafness dystonia protein 1 affect mitochondrial morphology

AU - Engl, Gertraud

AU - Florian, Stefan

AU - Tranebjærg, Lisbeth

AU - Rapaport, Doron

N1 - © The Author 2011. Published by Oxford University Press. All rights reserved.

PY - 2012/1

Y1 - 2012/1

N2 - Deafness-Dystonia-Optic Neuropathy (DDON) Syndrome is a rare X-linked progressive neurodegenerative disorder resulting from mutations in the TIMM8A gene encoding for the deafness dystonia protein 1 (DDP1). Despite important progress in identifying and characterizing novel mutations in this gene, little is known about the underlying pathomechanisms. Deficiencies in the biogenesis of hTim23 and consecutive alterations in biogenesis of inner membrane and matrix proteins have been proposed to serve as one possible mechanistic explanation. To shed new light on the role of DDP1 in the biogenesis of mammalian mitochondria, we investigated the effects of reduced or elevated DDP1 levels on mitochondrial dynamics and function. Our results show a reduction in the import of β-barrel proteins into mitochondria from cells overexpressing DDP1. This effect was not observed when the DDON-related mutant form DDP1-C66W was overexpressed. Live cell microscopy of primary fibroblasts derived from DDON patients and of DDP1 downregulated HeLa cells displayed alterations of mitochondrial morphology with notable extensions in the length of mitochondrial tubules, whereas overexpression of DDP1 induced the formation of hollow spherical mitochondria. Of note, knockdown of the TIMM8A gene by RNA interference did not show an influence on the oxygen respiration rate and the mitochondrial membrane potential. Taken together, these results suggest that alterations in the levels of DDP1 can affect the morphology of mitochondria and thus shed new light on the pathogenic mechanisms of DDON.

AB - Deafness-Dystonia-Optic Neuropathy (DDON) Syndrome is a rare X-linked progressive neurodegenerative disorder resulting from mutations in the TIMM8A gene encoding for the deafness dystonia protein 1 (DDP1). Despite important progress in identifying and characterizing novel mutations in this gene, little is known about the underlying pathomechanisms. Deficiencies in the biogenesis of hTim23 and consecutive alterations in biogenesis of inner membrane and matrix proteins have been proposed to serve as one possible mechanistic explanation. To shed new light on the role of DDP1 in the biogenesis of mammalian mitochondria, we investigated the effects of reduced or elevated DDP1 levels on mitochondrial dynamics and function. Our results show a reduction in the import of β-barrel proteins into mitochondria from cells overexpressing DDP1. This effect was not observed when the DDON-related mutant form DDP1-C66W was overexpressed. Live cell microscopy of primary fibroblasts derived from DDON patients and of DDP1 downregulated HeLa cells displayed alterations of mitochondrial morphology with notable extensions in the length of mitochondrial tubules, whereas overexpression of DDP1 induced the formation of hollow spherical mitochondria. Of note, knockdown of the TIMM8A gene by RNA interference did not show an influence on the oxygen respiration rate and the mitochondrial membrane potential. Taken together, these results suggest that alterations in the levels of DDP1 can affect the morphology of mitochondria and thus shed new light on the pathogenic mechanisms of DDON.

KW - Deafness

KW - Genetic Diseases, X-Linked

KW - HeLa Cells

KW - Humans

KW - Membrane Transport Proteins

KW - Mitochondria

KW - Polymerase Chain Reaction

KW - RNA Interference

U2 - 10.1093/hmg/ddr458

DO - 10.1093/hmg/ddr458

M3 - Journal article

C2 - 21984432

SN - 0964-6906

VL - 21

SP - 287

EP - 299

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 2

ER -